XIX International Symposium on Neonatology (Sao Paulo 2013) · 2016. 6. 27. · SAO PAULO 2013 22 . Resuscitation Pilot Studies in Extremely Preterm Infants Neonatal Research Group

Titrating oxygen needs in the delivery room in extremely preterm infants.

Máximo Vento MD PhD Professor of Pediatrics

Division of Neonatology & Health Research Institute University and Polytechnic Hospital La Fe

(Valencia; Spain)

XIX International Symposium on Neonatology (Sao Paulo 2013)

Scheme

• Basic concepts:

– Oxygen & oxidative stress & biomarkers

– Arterial oxygen saturation

• Oxygen in the fetal life & in the fetal-to-neonatal transition.

• Is it feasible to use lower FiO2 in preterm infants?

• Defining a reference range for postnatal SpO2.

• High versus low iFiO2: updated review & meta-analysis.

• Optimizing oxygenation in the DR in preterm.

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Basic concepts

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Glucose PEP

PYRUVATE

PYR

AcCoA

2ATP

TCA

SDH

CIII

CV

CI C IV UQ

C

CO2

CO2 H+

ADP

36ATP ATP synthase

NADH

NADH NAD+

H+ H+ H+

O2 H2O

Δψm

Fatty acids

Amino acids

PDH

LACTATE

Mitochondria

Cytoplasm 4 SAO PAULO 2013

Glucose (C6) Palmytic acid (C16)

Glycolysis 2 0

Krebs’ Cycle 2 8

Electron Transport Chain

32-34 121

TOTAL ATP formed 36-38 129

Aerobic vs. Anaerobic Metabolism: energetic balance

5 SAO PAULO 2013

+ + +

+

+ + +

+

+ + +

+

+ + +

+

Ground state di-Oxygen

Dröge W Physiol Rev 2002 6 SAO PAULO 2013

·O· ·O·

O2¯•

H2O2

OH•

O2

e¯

e¯

e¯

e¯

Superoxide

Hydrogen peroxide

Hydroxyl

Stepwise reduction of di-oxygen

4e¯

Adopted from Maltepe E et al Pediatr Res 2009

NO•

ONOO¯

Peroxynitrite

Fe++

7 SAO PAULO 2013

H2O + O2 GPx; CAT; PRx

PRx

GSH; TRx; CysSH

SOD

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Free radicals

Signaling molecules -Smooth muscle relaxation -Immunological function -EPO and HIF factors -Control of respiration

Damage cell constituents -DNA/RNA -Lipids -Proteins -Glycids Redox regulation

(GSH/GSSG) (L-cys/Cys-SS)

TRX-SH/TRX-SS

Oxygen saturation as measured by arterial pulse oximetry (SpO2)

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SAO PAULO 2013

Wavelength absorption and transmission for Hb and HbO2

Sola A et al An Pediatr 2005

Absorption of light when passing through tissue. Without motion the only variable

light absorption is by the arterial pulsatility

How does pulse oximeter function?

10

SAO PAULO 2013 Richmond & Goldsmith Clin Perinatol 2006

Relationship between paO2 and SpO2

11

Pulse oximetry

• CONCEPTS

– Arterial oxygen saturation (SpO2) represents the amount (g) of available Hb which are carrying O2.

– O2 content in blood: % O2Sat x [Hb/g] x 1.36 (ml/dl)

– Supply of O2 to tissue depends also on cardiac output and regional blood flow.

– Confidence limits of SpO2 is ±3% for SpO2>70% and greater for SpO2

Pulse oximetry

• OPTIMIZING FUNCTIONALITY

– Adequate training

– Connecting the probe first to the patient and then to the oximeter (O’Donnell C et al 2007)

– Using shorter averaging intervals (2 sec), maximal sensitivity, and PO’s with motion artifact rejection (Rich W et al Clin Perinatol 2010)

– Setting the probe on the right wrist (pre-ductal)

– Protecting the probe from the light

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Oxygen in utero and in the fetal-to-neonatal transition

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8 10 12 14 16 20 24 28 32 36

100%

80%

60%

40%

20%

50%

Inte

rvill

ou

s o

xyge

n t

ensi

on

(m

m H

g)

Gestational age (weeks)

Oxygen saturation in utero during fetal development

Schneider H. Respir Physiol Neurobiol 2011

0

2

4

6

8

10

12

14

16

Non laboring Laboring

Veno-arterial difference (ml/dl) Fetal oxygen delivery (ml/min/kg)

Fetal oxygen uptake (ml/min/kg)

Umbilical cord analysis of parameters of oxygen metabolism

Acharya G et al SJOG 2009

NS

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Forkner et al Anesthesiology 2007

Maternal oxygen administration: fetal response

p

Khaw KS et al BJ Anaesth 2002

Maternal oxygen administration: fetal response.

Um

bili

cal v

eno

us

paO

2 (

kPa)

8

7

6

5

4

3

10 20 30 40 50

Maternal arterial pO2 (kPa)

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Khaw KS et al BJ Anaesth 2002

Maternal oxygen administration: fetal response

MDA 8-ISOPROSTANES

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Is it feasible to use use lower initial iFO2 in extremely low birth weight

infants?

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PILOT STUDIES USING LOWER OXYGEN IN PRETERM (n= 506)

Reference Year Design N iFIO2 Aim Conclusions

Harling AE et al 2005 RCT; < 31 wks.

No blender; no P-Ox

No TSpO2

52 50 vs. 100% Reduce lung

inflammation

No differences in lung

inflammation. Feasible to

resuscitate with lower FIO2

Dawson JA et al 2007 Cohort study; < 30

wks

Blender; P-Ox;

TspO2

43 21% vs. 100% Feasibility study O2 supplementation needed

in room air group. Feasible

to resuscitate with lower

FIO2 if titrated.

Stola A et al 2009 Cohort vs practice

plan

< 1500 g.

Blender; P-Ox;

TSpO2

100 Variable vs.

100%

Feasibility study

Reduce paO2 at

admission to NICU

Feasible to initiate with

lower FIO2 if titrated.

Change associated with

lower paO2 at admission to

NICU.

Rabi J et al 2009 RCT; < 32 wks.

Blender; P-Ox;

TSpO2

106 100 % vs.

100% + titrated

vs. 21% +

titrated

Feasibility study

Target SpO2 85-92%

Both groups needed similar

FIO2 to attain targeted

saturation.

Escrig R et al

Vento M et al

2008

2009

RCT; ≤ 28 wks.

Blender; P-Ox;

TSpO2

120 30% vs. 90% Feasibility study

Target SpO2 85%

Oxidative stress

Inflammation

Feasible to initiate with

lower FIO2 with less

oxidative stress and

inflammation.

Wang CL et al 2008 RCT; < 32 wks.

Blender; P-Ox;

TSpO2

41 21% vs. 100% Feasibility study

Target SpO2 70-80%

No feasible to initiate with

room air; O2 supplements

needed.

Ezaki et al 2009 RCT; ≤ 29 wks.

Blender; P-Ox;

TSpO2

44 Titrated vs.

100%

Oxidative stress Increased oxidative stress in

100% group.

Vento M JNPM 2010 21 SAO PAULO 2013

Relevant features of oxygen studies in preterm

• Use of preductal pulse oximetry

• Target saturation at specific postnatal timing

• Use of air/oxygen blender to adjust FiO2 according to SpO2 readings.

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Resuscitation Pilot Studies in Extremely Preterm Infants Neonatal Research Group HUiP La Fe (Valencia)

• 2 randomized controlled clinical trials (nT =120

• Inclusion ≤ 28 weeks gestation needing active maneuvers to achieve successful adaption.

• DR management

– Blender randomly assigned to FiO2 30% or 90%

– Preductal pulse oximetry

– Adjustments according to HR, SpO2, reactivity

– Ventilation strategies according to S.E.N. guidelines 2007

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Low Oxygen

(n=56)

High Oxygen

(n=64)

Gestational age (weeks) , mean ± standard deviation 26.0 ± 1.5* 26.3 ± 1.3*

Birth weight (grams), mean ± standard deviation 854.7 ± 170.1* 901.7 ± 195.4*

Gender, n

Male

Female

14

23

18

23

Multiple birth, n 11 9

Prenatal corticosteroid therapy (full schedule), n (%) 36 (97.2%) 38 (92.7%)

Type of Delivery, n

Vaginal (percentage)

Cesarean section (%)

18 (48.6%)

19 (51.4%)* 17 (41.4%)

24 (58.6%)*

Cord blood pH at birth 7.05 ± 0.9* 7.09 ± 1.1*

Apgar score median (interquartile range)

1 min

5 min

5 (2-7)* 8 (5-9)

6 (2-8)* 8 (5-9)

Received supplementary oxygen during resuscitation, n (%) 32 (86.5%)** 34 (82.9%)**

Tracheal intubation in the Delivery Room, n (%) 21 (56.7%)** 25 (60.9%)**

Breathing 21% Oxygen at arrival to the NICU, n (%) 28 (75.6%)* 23 (56.0%)**$

POPULATION & DR MANAGEMENT

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FIO2 HEART RATE

** ** **

** **

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□ Low Oxygen (initial FiO2 : 30%)

▲High Oxygen (initial FiO2: 90%)

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◊ Low Oxygen (initial FiO2 : 30%) ▲High Oxygen (initial FiO2: 90%)

**

##

#

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O-tyr/Phenyl ratio 8oxdG/2dG ratio

**

**

**

**

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■ Control ; □ Hox; ▲ Lox

Isofurans

**

**

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◊ Control ; □ Hox; ▲ Lox

HYPEROXIA DERIVED OXIDATIVE STRESS MARKERS ASSOCIATED WITH BPD

0

40

80

120

160

BPD NO BPD

GSSG day 3 Iso F day 7

12.0

9.0

6.0

3.0

GS

SG

(n

g/m

l)

Iso

Fu (n

g/m

g d

e c

rea

tinin

e)

** **

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HYDROXYL RADICAL DERIVED OXIDATIVE STRESS MARKERS

ASSOCIATED WITH BPD

0

5

10

15

20

BPD NO BPD

O-tyr/phenyl day 7 8oxodG/2dg day 7

40.0

30.0

20.0

10.0

O-t

yr/

Ph

en

yl 8

-ox

od

G/2

dG

** **

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Defining the reference range for SpO2 in term and preterm infants

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SAO PAULO 2013

25

50

75

100

Term fetal-to-neonatal transition: Arterial partial pressure of oxygen (paO2)

IU TRANSITION POST-NATAL

Vento M et al J Pediatr 2003

33

mmHg

Pulse oximetry in the first minutes of life (term newborn)

Vento M & Saugstad OD 2010

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0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20

Time after birth (min)

Pre

du

ctal

Sp

O2

(%

) SpO2 in ELGA neonates ≤ 28 weeks gestation (n=29)

Vento M & Saugstad OD SFN M 2010.

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SpO2 polynomial adjustment curve (± std) in “control” ELGA neonates (≤ 28 weeks gestation) (n=29).

Vento M, Saugstad OD SFNM 2010 SAO PAULO 2013

36

Data acquisition system

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Method

• Combined pulse oximetry data from three data sets

• Dawson JA (unpublished) n=230

• Kamlin et al J Pediatr 2006 n=175

• Vento M (unpublished) n=20 (≤ 28 weeks gestation)

• Pre-ductal sensor location

• 2 second averaging, maximum sensitivity

• Masimo Radical®

Dawson JA et al Pediatrics 2010 SAO PAULO 2013

38

JA Dawson O Kamlin (and Jr!)

Data set characteristics

160 (34%) 308 (66%)

Dawson Ja et al Pediatrics 2010 SAO PAULO 2013

39

01

02

03

04

05

06

07

08

09

01

00

Oxyge

n s

atu

ratio

n (

%)

1 2 3 4 5 6 7 8 9 10minutes from birth

10-90th centile median

Term Neonates > 37 weeks gestation

Dawson Ja et al Pediatrics 2010 SAO PAULO 2013 40

01

02

03

04

05

06

07

08

09

01

00

Oxyge

n s

atu

ratio

n (

%)

1 2 3 4 5 6 7 8 9 10minutes from birth

10-90th centile median

Preterm < 37 weeks gestation

Dawson Ja et al Pediatrics 2010 SAO PAULO 2013

41

Use of centiles in the delivery room

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How could SpO2 centiles be used to inform decision making in the DR?

• To date centile chart provides the best target range during resuscitation.

• For any given centile (e.g.: 50%) this percentage of normal babies (50%) will have an SpO2 below this level.

• If the centile chosen as target is too high, a great percentage of babies will unnecessarily receive oxygen supplementation.

• If the centile chosen is too low, babies could easily be exposed to hypoxemia.

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Suggested level for administration of oxygen0

10

20

30

40

50

60

70

80

90

100

Oxyg

en

sa

tura

tio

n(%

)

0 1 2 3 4 5 6 7 8 9 10

Minutes after birth

10th 25th 50th 75th 90th

How could SpO2 centiles be used to inform decision making in the DR?


10

20

30

40

50

60

70

80

90

100

Oxyge

n s

atu

ration

(%)

0 1 2 3 4 5 6 7 8 9 10

Minutes after birth



10

20

30

40

50

60

70

80

90

100

Oxyge

n s

atu

ration

(%)

0 1 2 3 4 5 6 7 8 9 10

Minutes after birth


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The Transitional Oxygen Tracking System (TOTS)

NN Finer & W Rich & Tina A Leone (UCSD; San Diego; USA)

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25

35

45

55

65

75

85

95

0 2 4 6 8 10 12 14 16 18 20

Pre

du

cta

l S

pO

2 (

%)

Time after birth (min)

Titration of FiO2 against measured SpO2

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Courtesy of NN Finer & W Rich (San Diego; USA)

TRANSITIONAL OXYGEN TRACKING SYSTEM

50%

10%

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TRANSITIONAL OXYGEN TRACKING SYSTEM


FiO2 adjustments in 10% intervals according to oximeter readings

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Oxygen saturation in preterm with CPAP + air Comparison with Dawson’s nomogram

Vento M et al ADC FNE 2012

What initial FiO2 is best for ELGA neonates in the delivery room?

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High vs. low iFiO2 : systematic review

• 6 Studies randomized or “quasi” randomized controled trials including 484 preterm newborn infants were identified.

• iFiO2 50%

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Brown JVE et al PLoS ONE 2012

• Primary outcomes

– Mortality before hospital discharge.

– Neurocognitive development at >12 m

– Disability classification and results of cognitive and educational evaluation at > 5 years of age.

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Study (year)

Place Method Participants Comparison

Harling 2005 Liverpool RU RC

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SECONDARY OUTCOMES N= assays (participants) RR

Tracheal intubation 3 (225) 0.97 (0.72, 1.29)

Surfactant reposition 3 (188) 1.03 (0.68, 1.58)

Reaching SpO2 at (min):

3 min 1 (106) 0.42 (0.10, 1.83)

5 min 2 (184) 0.94 (0.80, 1.11)

10 min 3 (231) 0.96 (0.84, 1.11)

EPC/DBP 3 (223) 0.86 (0.62, 1.18)

ROP 3 (199) 0.68 (0.24, 1.96)

NEC 3 (199) 1.74 (0.42, 7.20)

IPVH- GRADES III/IV 4 (240) 1.50 (0.71, 3.15)


• CONCLUSIONS

– There is a tendency towards reduction in mortality (20%) in preterm with iFiO2

Optimizing oxygenation of ELBW infants in the delivery room:

practical approach!

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Optimizing oxygenation in ELBW infants

• Place preductal PO2 sensor (60-90 sec)

• Start in 21-40% FiO2 with adequate flow (4-8 l/min) and always use an air/oxygen blender.

• Aerate lungs to promptly achieve Functional Residual Capacity (FRC)

– Continuous positive pressure 4-6 cmH2O

– PIP 20-25 / PEEP 4-5 cmH2O

SAO PAULO 2013 59

SAO PAULO 2013 60 Fuchs H et al Neoreviews 2012

Vento M editor: Non-invasive ventilation in the DR: NeoReviews 2012

Optimizing oxygenation in ELBW infants

• At 90s review the infant’s HR, SpO2 and breathing efforts

– If the baby is breathing, or is well ventilated, and HR is rising, and SpO2 > 10th OXYGEN is not required.

– If O2 is needed, FiO2 should be titrated against SpO2 to be kept within established centiles.

– SpO2 < 10th and/or HR is not rising or continues to fall increase FiO2 until SpO2 fits within centiles.

– Wait at least 15 sec after each change and be sure the mask is well placed (use colorimetric assessment??)

– If SpO2 > 90th reduce FiO2.

• Continue titrating FiO2 according to infant’s response. SAO PAULO 2013

61

PRETERM DELIVERY

Good responder

PROFILE >27 wks female

HR response +++ Cry +

Activity + A. Steroids +

Uncertain

PROFILE 25/0-26/6 wks/d

male/female HR delayed response Weak cry; high pitch Scarce movements

A. Steroids +

Bad responder

PROFILE

ANCONA 2013 63

Neonatal Research Group University & Polytechnic Hospital La Fe

(Valencia; Spain)

Documents

XIX International Symposium on Neonatology (Sao Paulo 2013) · 2016. 6. 27. · SAO PAULO 2013 22 . Resuscitation Pilot Studies in Extremely Preterm Infants Neonatal Research Group